EP1619180A4 - Casr-antagonist - Google Patents

Casr-antagonist

Info

Publication number
EP1619180A4
EP1619180A4 EP04729243A EP04729243A EP1619180A4 EP 1619180 A4 EP1619180 A4 EP 1619180A4 EP 04729243 A EP04729243 A EP 04729243A EP 04729243 A EP04729243 A EP 04729243A EP 1619180 A4 EP1619180 A4 EP 1619180A4
Authority
EP
European Patent Office
Prior art keywords
compound
calcium
casr antagonist
formula
antagonist
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP04729243A
Other languages
English (en)
French (fr)
Other versions
EP1619180A1 (de
EP1619180B1 (de
Inventor
Yuko Shinagawa
Teruhiko Inoue
Toshihiro Kiguchi
Taku Ikenogami
Naoki Ogawa
Kenji Fukuda
Takashi Nakagawa
Masanori Shindo
Yuki Soejima
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Japan Tobacco Inc
Original Assignee
Japan Tobacco Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Japan Tobacco Inc filed Critical Japan Tobacco Inc
Priority to EP09177717A priority Critical patent/EP2189439A3/de
Priority to PL04729243T priority patent/PL1619180T3/pl
Priority to EP10179435.2A priority patent/EP2308828A3/de
Priority to SI200431348T priority patent/SI1619180T1/sl
Publication of EP1619180A1 publication Critical patent/EP1619180A1/de
Publication of EP1619180A4 publication Critical patent/EP1619180A4/de
Application granted granted Critical
Publication of EP1619180B1 publication Critical patent/EP1619180B1/de
Priority to CY20101100234T priority patent/CY1109880T1/el
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Furan Compounds (AREA)
EP04729243A 2003-04-23 2004-04-23 CaSR-ANTAGONIST Expired - Lifetime EP1619180B1 (de)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP09177717A EP2189439A3 (de) 2003-04-23 2004-04-23 CaSR-Antagonist
PL04729243T PL1619180T3 (pl) 2003-04-23 2004-04-23 ANTAGONISTA CaSR
EP10179435.2A EP2308828A3 (de) 2003-04-23 2004-04-23 CaSR-Antagonist
SI200431348T SI1619180T1 (sl) 2003-04-23 2004-04-23 Antagonist CaSR
CY20101100234T CY1109880T1 (el) 2003-04-23 2010-03-10 ΑΝΤΑΓΩΝΙΣΤΗΣ CaSR

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003119131 2003-04-23
PCT/JP2004/005886 WO2004094362A1 (ja) 2003-04-23 2004-04-23 CaSRアンタゴニスト

Publications (3)

Publication Number Publication Date
EP1619180A1 EP1619180A1 (de) 2006-01-25
EP1619180A4 true EP1619180A4 (de) 2006-05-24
EP1619180B1 EP1619180B1 (de) 2009-12-16

Family

ID=33308093

Family Applications (3)

Application Number Title Priority Date Filing Date
EP09177717A Withdrawn EP2189439A3 (de) 2003-04-23 2004-04-23 CaSR-Antagonist
EP10179435.2A Withdrawn EP2308828A3 (de) 2003-04-23 2004-04-23 CaSR-Antagonist
EP04729243A Expired - Lifetime EP1619180B1 (de) 2003-04-23 2004-04-23 CaSR-ANTAGONIST

Family Applications Before (2)

Application Number Title Priority Date Filing Date
EP09177717A Withdrawn EP2189439A3 (de) 2003-04-23 2004-04-23 CaSR-Antagonist
EP10179435.2A Withdrawn EP2308828A3 (de) 2003-04-23 2004-04-23 CaSR-Antagonist

Country Status (31)

Country Link
US (4) US7304174B2 (de)
EP (3) EP2189439A3 (de)
JP (1) JP3751312B2 (de)
KR (1) KR100696927B1 (de)
CN (2) CN101723921A (de)
AR (1) AR044075A1 (de)
AT (1) ATE452121T1 (de)
AU (1) AU2004232604C1 (de)
BR (1) BRPI0407097A (de)
CA (1) CA2513738C (de)
CL (1) CL2004000868A1 (de)
CO (1) CO5640091A2 (de)
CY (1) CY1109880T1 (de)
DE (1) DE602004024668D1 (de)
DK (1) DK1619180T3 (de)
ES (1) ES2337576T3 (de)
HK (1) HK1083096A1 (de)
HR (1) HRP20100042T1 (de)
IL (1) IL169575A (de)
MX (1) MXPA05007609A (de)
MY (1) MY138734A (de)
NO (1) NO20054868L (de)
NZ (1) NZ541188A (de)
PE (1) PE20050460A1 (de)
PL (1) PL1619180T3 (de)
PT (1) PT1619180E (de)
RU (1) RU2315036C2 (de)
SI (1) SI1619180T1 (de)
TW (1) TWI329628B (de)
WO (1) WO2004094362A1 (de)
ZA (1) ZA200505587B (de)

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US20070155819A1 (en) * 2004-02-06 2007-07-05 Marquis Robert W Jr Calcilytic compounds
WO2007124465A2 (en) * 2006-04-20 2007-11-01 Amgen Inc. Stable emulsion formulations
WO2008121386A2 (en) 2007-03-30 2008-10-09 Amgen Inc. Calcimimetic compounds for use in the treatment of bowel disorders
EP2292592B1 (de) * 2008-06-05 2012-09-05 Asahi Kasei Pharma Corporation Sulfonamidverbindung und ihre anwendung
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RU2478616C2 (ru) * 2008-12-24 2013-04-10 Дайити Санкио Компани, Лимитед Циклические аминосоединения
WO2010104882A1 (en) 2009-03-10 2010-09-16 Amgen Inc. Methods of modulating sperm motility
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CN102365261A (zh) * 2009-03-26 2012-02-29 日本烟草产业株式会社 制备羧酸化合物的方法
WO2010113860A1 (ja) * 2009-03-31 2010-10-07 第一三共株式会社 ビフェニル－環状アミン化合物
CA2762137A1 (en) 2009-05-27 2010-12-02 Leo Pharma A/S Novel calcium sensing receptor modulating compounds and pharmaceutical use thereof
US8785494B2 (en) 2009-05-27 2014-07-22 Leo-Pharma A/S Calcium sensing receptor modulating compounds and pharmaceutical use thereof
US20130267516A1 (en) * 2010-11-26 2013-10-10 Leo Pharma A/S Substituted cyclopentyl-azines as casr-active compounds
RU2013128973A (ru) 2010-11-26 2015-01-10 Лео Фарма А/С Соединения, активные в отношении кальций-чувствительных рецепторов
US20130261132A1 (en) 2010-11-26 2013-10-03 Leo Pharma A/S Calcium-sensing receptor-active compounds
US20130244995A1 (en) 2010-11-26 2013-09-19 Leo Pharma A/S Calcium-sensing receptor-active compounds
GB201113538D0 (en) * 2011-08-04 2011-09-21 Karobio Ab Novel estrogen receptor ligands
US9227919B2 (en) * 2012-08-27 2016-01-05 Lupin Limited Arylalkylamine compounds as calcium sensing receptor modulators
WO2017215591A1 (en) 2016-06-13 2017-12-21 Syneurx International (Taiwan) Corp. Use of lithium benzoate for treating central nervous system disorders
BR112022011127A2 (pt) * 2019-12-09 2022-08-23 Beijing Tuo Jie Biopharmaceutical Co Ltd Composto agonista do receptor de detecção de cálcio e aplicação do mesmo
CN116648243A (zh) 2020-08-04 2023-08-25 柯西立提克斯疗法有限公司 三苯基钙敏感化合物的制剂
EP4213829A1 (de) 2020-09-18 2023-07-26 Calcilytix Therapeutics, Inc. Triphenylcalzilytische verbindungen zur behandlung von autosomaler dominanter hypocalcämie typ 1 (adh1)

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2002014259A1 (fr) * 2000-08-11 2002-02-21 Japan Tobacco Inc. Antagonistes du recepteur de calcium
WO2004106280A1 (ja) * 2003-05-28 2004-12-09 Japan Tobacco Inc. ＣａＳＲアンタゴニスト

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Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2002014259A1 (fr) * 2000-08-11 2002-02-21 Japan Tobacco Inc. Antagonistes du recepteur de calcium
WO2004106280A1 (ja) * 2003-05-28 2004-12-09 Japan Tobacco Inc. ＣａＳＲアンタゴニスト

Also Published As

Publication number Publication date
EP2308828A3 (de) 2013-05-22
CN1741984A (zh) 2006-03-01
US20090326058A1 (en) 2009-12-31
TWI329628B (en) 2010-09-01
US20080255042A1 (en) 2008-10-16
AU2004232604A8 (en) 2004-11-04
NO20054868D0 (no) 2005-10-21
AU2004232604B2 (en) 2007-09-13
MXPA05007609A (es) 2005-09-30
AU2004232604C1 (en) 2008-06-05
HK1083096A1 (en) 2006-06-23
IL169575A0 (en) 2007-07-04
NO20054868L (no) 2005-12-20
US20120301552A1 (en) 2012-11-29
CY1109880T1 (el) 2014-09-10
DK1619180T3 (da) 2010-03-29
ZA200505587B (en) 2006-09-27
EP1619180A1 (de) 2006-01-25
MY138734A (en) 2009-07-31
KR20050094047A (ko) 2005-09-26
CA2513738A1 (en) 2004-11-04
AU2004232604A1 (en) 2004-11-04
DE602004024668D1 (de) 2010-01-28
CN101723921A (zh) 2010-06-09
IL169575A (en) 2011-07-31
AU2004232604B8 (en) 2004-11-04
KR100696927B1 (ko) 2007-03-20
WO2004094362A1 (ja) 2004-11-04
JP3751312B2 (ja) 2006-03-01
RU2005123985A (ru) 2006-01-27
PE20050460A1 (es) 2005-07-08
PT1619180E (pt) 2009-12-29
PL1619180T3 (pl) 2010-05-31
CA2513738C (en) 2010-04-06
CL2004000868A1 (es) 2005-01-21
AR044075A1 (es) 2005-08-24
CO5640091A2 (es) 2006-05-31
SI1619180T1 (sl) 2010-04-30
BRPI0407097A (pt) 2006-01-24
EP2308828A2 (de) 2011-04-13
ATE452121T1 (de) 2010-01-15
US7304174B2 (en) 2007-12-04
EP2189439A3 (de) 2011-05-04
CN100577633C (zh) 2010-01-06
TW200505823A (en) 2005-02-16
EP2189439A2 (de) 2010-05-26
NZ541188A (en) 2008-01-31
RU2315036C2 (ru) 2008-01-20
EP1619180B1 (de) 2009-12-16
US20050032796A1 (en) 2005-02-10
HRP20100042T1 (hr) 2010-02-28
JPWO2004094362A1 (ja) 2006-07-13
ES2337576T3 (es) 2010-04-27

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